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Processes for Constructing Homogeneous Antibody Drug Conjugates



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Antibody drug conjugates (ADCs) are synthesized by conjugating a cytotoxic drug or “payload” to a monoclonal antibody. The payloads are conjugated using amino or sulfhydryl specific linkers that react with lysines or cysteines on the antibody surface. A typical antibody contains over 60 lysines and up to 12 cysteines as potential conjugation sites. The desired DAR (drugs/antibody ratio) depends on a number of different factors and ranges from two to eight drugs/antibody. The discrepancy between the number of potential conjugation sites and the desired DAR, combined with use of conventional conjugation methods that are not site-specific, results in heterogeneous ADCs that vary in both DAR and conjugation sites. Heterogeneous ADCs contain significant fractions with suboptimal DARs that are known to possess undesired pharmacological properties. As a result, new methods for synthesizing homogeneous ADCs have been developed in order to increase their potential as therapeutic agents. This article will review recently reported processes for preparing ADCs with improved homogeneity. The advantages and potential limitations of each process are discussed, with emphasis on efficiency, quality, and in vivo efficacy relative to similar heterogeneous ADCs.

Table 1. Examples of Heterogeneous ADCs Currently in Clinical Trials for Cancer Indicationsa
ADC Sponsor Indications Status Payload Linked to Target
Adcetris Seattle Genetics HL and ALCL approved MMAE cysteine CD30
Kadcyla Genentech/Roche breast cancer approved DM1 lysine Her2
inotuzumab ozogamicin Pfizer NHL and ALL Phase III calicheamicin lysine CD22
lorvotuzumab mertansine Immunogen SCLC Phase II DM1 lysine CD56
glembatumumab vedotin Celldex BC, melanoma Phase II MMAE cysteine GPNMB
PSMA-ADC Progenics prostate Phase II MMAE cysteine FOLH1
SAR-3419 Sanofi DLBCL, ALL Phase II DM4 lysine CD19
ABT-414 Abbvie glioblastoma Phase II MMAE cysteine EGFR
BT-062 Biotest mult. myeloma Phase II DM4 lysine CD138
HLL1-Dox Immunomedics CLL, MM, NHL Phase II doxorubicin cysteine CD74
Immu-130 Immunomedics CRC Phase II SN-38 cysteine CEACAM5
Immu-132 Immunomedics solid tumors Phase II SN-38 cysteine EGP1
SYD985 Synthon breast cancer Phase II duocarmycin cysteine Her2
SAR-3419 Sanofi DLBCL, ALL Phase II DM4 lysine CD19
IMGN853 ImmunoGen solid tumors Phase I DM4 lysine FOLR1
IMGN529 ImmunoGen BCL,CLL, NHL Phase I DM1 lysine CD37
ASG-22M6E Astellas solid tumors Phase I MMAE cysteine nectin-4
AGS-16M8F Astellas RCC Phase I MMAF cysteine AGS16
AMG 172 Amgen RCC Phase I DM1 lysine CD27L
AMG 595 Amgen glioblastoma Phase I DM1 lysine EGFR8
BAY94-9343 Bayer solid tumors Phase I DM4 lysine mesothelin

Processes for Constructing Homogeneous Antibody Drug Conjugates

Igenica Biotherapeutics, 863A Mitten Road, Suite 100B, Burlingame, California 94010, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00067
Publication Date (Web): April 14, 2016
Copyright © 2016 American Chemical Society
*Igenica Biotherapeutics 863A Mitten Road, Suite 100B Burlingame, CA 94010, USA. E-mail: Cell: 650-339-3948.
ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

//////Processes, Constructing,  Homogeneous,  Antibody Drug Conjugates

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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